Does treating with anti–PD-1 to improve glomerular health come without a cost? Reply.
Authors: Stuart J. Shankland, Jeffrey W. Pippin, Oliver Wessely
Journal: Journal of Clinical Investigation (2022)

As representatives for our entire team, we thank Jhaveri et al. (1) for their insightful comments on our recent study investigating the increased expression of programmed cell death protein 1 (PD-1) in kidneys during aging and focal segmental glomerulosclerosis (FSGS) (2).In our manuscript, we showed that PD-1 was predominantly increased in podocytes and kidney tubular epithelial cells in both mice and humans.Moreover, in humans, age-elevated glomerular PCDC1 (gene encoding human PD-1) levels were associated with a lower estimated glomerular filtration rate (eGFR), increased segmental glomerulosclerosis, and reduced arterial intima-to-lumen ratio.We also demonstrated a mechanistic link between increased PD-1 levels in podocytes and their shortened life span.Finally, specifically antagonizing the PD-1 pathway with a specific anti-PD-1 antibody (similar to humanized pembrolizumab or nivolumab) in aged mice and mice with experimental FSGS had major benefits on kidney histology, podocyte life and health span, and tubular epithelial injury (2).In their response, Jhaveri and colleagues, experts in onconephrology, eloquently discuss the clinical kidney-specific adverse events (AEs) when using immune checkpoint inhibitors (ICI) in cancer patients (1).They provide important clinical insights and an up-to-date summary of the incidence and types of glomerular lesions, acute kidney injury, and acute interstitial nephritis observed in patients receiving ICI for cancer treatment (3, 4).Importantly, complete or partial remission of kidney-specific AEs upon discontinuation of ICI treatment in a subset of patients suggests a causal link (3, 4).We unreservedly agree with Jhaveri et al. that caution is warranted when using ICI clinically.In fact, we have not advocated the clinical use of anti-PD-1 treatment to limit or reverse kidney aging, nor to be used as a therapy for FSGS.The clinical data highlighted by Jhaveri et al. underscore the importance of gaining a better understanding of the mechanism or mechanisms underlying kidney complications in patients.While T cell activation, proliferation, and subsequent kidney infiltration are suspected to contribute (3, 4), how this cumulates into kidney dysfunction is unknown.ICIs block the CTLA-4 and/or PD-1 pathways.CTLA-4 acts early in tolerance induction, stopping potentially autoreactive T cells at the initial stage of naive T cell activation, while PD-1 acts late to maintain long-term tolerance, primarily in peripheral tissues (5).Typically a lower incidence of AEs is associated with PD-1 blockade compared with CTLA-4 blockade (3, 4).Interestingly, in our study, mouse Ctla4 mRNA levels, in contrast with PD1, were not elevated in podocytes with age.There are also several differences between humans and mice that may influence the response to anti-PD-1 treatments.To reconcile these, one needs to experimentally align the animal studies with the therapeutic scenario in human cancer patients.Possible considerations include the following: (a) the duration of therapyin our study, mice received eight weeks of treatment, while human patients typically receive a 13-week median drug exposure before glomerular disease is first detected; (b) comorbid conditions are oftentimes present in humans (e.g., patients